Transgelin exacerbates pulmonary artery smooth muscle cell dysfunction in shunt-related pulmonary arterial hypertension.
ESC Heart Fail
; 9(5): 3407-3417, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35841124
ABSTRACT
AIMS:
Orchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH. METHODS ANDRESULTS:
Transgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n = 12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group 18.2 ± 5.1 vs. 13.6 ± 2.6%, P < 0.05; irreversible group vs. control group 29.9 ± 4.7 vs. 13.6 ± 2.6%, P < 0.001; irreversible group vs. reversible group 29.9 ± 4.7 vs. 18.2 ± 5.1, P < 0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r = 0.48, P = 0.03, n = 19). (ii) Compared with the normal control group (n = 12), TGF-ß1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group 14.8 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. control group 20.1 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. reversible group 20.1 ± 4.4 vs. 14.8 ± 4.4, P < 0.01). The progression-dependent correlation between TGF-ß1 and transgelin was demonstrated in CHD-PAH patients (r = 0.48, P = 0.04, n = 19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-ß1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects.CONCLUSIONS:
These results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-ß1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hipertensão Arterial Pulmonar
/
Hipertensão Pulmonar
Tipo de estudo:
Etiology_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ESC Heart Fail
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China